Modulation of the Antitumor Response to Metformin, Caffeine, and Sodium Dichloroacetate by the Hypoxic Microenvironment in Lung Cancer Cells.

Abstract

Metformin, caffeine, and dichloroacetate (DCA) have shown antitumor effects. The hypoxic tumor microenvironment can modulate drug response. We aimed to analyze the interaction of metformin with caffeine or DCA in lung cancer cells (HCC827) under normoxia and hypoxia conditions. Cell viability was evaluated using the crystal violet assay after individual and combined drug treatment under normoxia (21% O₂) and hypoxia (1% O₂) conditions. Combination effects were analyzed using isobolographic analysis. The results show that under normoxia conditions, the combination of metformin with DCA (γ = 0.98 ± 0.35, p > 0.05) or caffeine (γ = 0.90 ± 0.34, p > 0.05) revealed additivity. However, in hypoxia, both combinations exhibited significant antagonism, with γ values appearing greater than one for metformin + DCA (γ = 4.20 ± 1.44, p < 0.05) and metformin + caffeine (γ = 2.88 ± 0.90, p < 0.05). Hypoxia significantly alters the pharmacological interaction of metformin with caffeine or DCA, which could limit their combined therapeutic potential in hypoxic tumors despite metformin's activity in this environment. The importance of considering tumor oxygenation status in the design of combined therapies for lung cancer is emphasized.